tbuckley/cabot-search huggingface dataset:
Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies
Authors: Aleksandar Denic, Marija Bogojevic, Aidan F. Mullan, Moldovan Sabov, Muhammad S. Asghar, Sanjeev Sethi, Maxwell L. Smith, Fernando C. Fervenza, Richard J. Glassock, Musab S. Hommos, Andrew D. Rule
Journal: Journal of the American Society of Nephrology (2022)

Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment.We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria.Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis >50% in discriminating risk of ESKD or progressive CKD.Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.
A Phylogeny-aware GWAS Framework to Correct for Heritable Pathogen Effects on Infectious Disease Traits
Authors: Sarah Nadeau, Christian W Thorball, Roger Kouyos, Huldrych F Günthard, Jürg Böni, Sabine Yerly, Matthieu Perreau, Thomas Klimkait, Andri Rauch, Hans H Hirsch, Matthias Cavassini, Pietro Vernazza, Enos Bernasconi, Jacques Fellay, Venelin Mitov, Tanja Stadler, I Abela, K Aebi-Popp, A Anagnostopoulos, M Battegay, E Bernasconi, DL Braun, HC Bucher, A Calmy, M Cavassini, A Ciuffi, G Dollenmaier, M Egger, L Elzi, J Fehr, J Fellay, H Furrer, CA Fux, HF Günthard, A Hachfeld, D Haerry, B Hasse, HH Hirsch, M Hoffmann, I Hösli, M Huber, CR Kahlert, L Kaiser, O Keiser, T Klimkait, RD Kouyos, H Kovari, K Kusejko, G Martinetti, de Tejada B Martinez, C Marzolini, KJ Metzner, N Müller, J Nemeth, D Nicca, P Paioni, G Pantaleo, M Perreau, A Rauch, P Schmid, R Speck, M Stöckle, P Tarr, A Trkola, G Wandeler, S Yerly
Journal: Molecular Biology and Evolution (2022)

Abstract Infectious diseases are particularly challenging for genome-wide association studies (GWAS) because genetic effects from two organisms (pathogen and host) can influence a trait. Traditional GWAS assume individual samples are independent observations. However, pathogen effects on a trait can be heritable from donor to recipient in transmission chains. Thus, residuals in GWAS association tests for host genetic effects may not be independent due to shared pathogen ancestry. We propose a new method to estimate and remove heritable pathogen effects on a trait based on the pathogen phylogeny prior to host GWAS, thus restoring independence of samples. In simulations, we show this additional step can increase GWAS power to detect truly associated host variants when pathogen effects are highly heritable, with strong phylogenetic correlations. We applied our framework to data from two different host–pathogen systems, HIV in humans and X. arboricola in A. thaliana. In both systems, the heritability and thus phylogenetic correlations turn out to be low enough such that qualitative results of GWAS do not change when accounting for the pathogen shared ancestry through a correction step. This means that previous GWAS results applied to these two systems should not be biased due to shared pathogen ancestry. In summary, our framework provides additional information on the evolutionary dynamics of traits in pathogen populations and may improve GWAS if pathogen effects are highly phylogenetically correlated amongst individuals in a cohort.
Clonal germinal center B cells function as a niche for T-cell lymphoma
Authors: Manabu Fujisawa, Tran B. Nguyen, Yoshiaki Abe, Yasuhito Suehara, Kota Fukumoto, Sakurako Suma, Kenichi Makishima, Chihiro Kaneko, Yen T.M. Nguyen, Kensuke Usuki, Kentaro Narita, Kosei Matsue, Naoya Nakamura, Shumpei Ishikawa, Fumihito Miura, Takashi Ito, Ayako Suzuki, Yutaka Suzuki, Seiya Mizuno, Satoru Takahashi, Shigeru Chiba, Mamiko Sakata-Yanagimoto
Journal: Blood (2022)

Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes the development of T follicular helper (TFH)-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development using mouse models and human samples. Among the 2 mouse models, mice lacking Tet2 in all the blood cells (Mx-Cre × Tet2flox/flox × G17V RHOA transgenic mice) spontaneously developed AITL for approximately up to a year, while mice lacking Tet2 only in the T cells (Cd4-Cre × Tet2flox/flox × G17V RHOA transgenic mice) did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. Single-cell RNA-sequencing (scRNA-seq) of &gt;50 000 cells from mouse and human AITL samples revealed significant expansion of aberrant B cells, exhibiting properties of activating light zone (LZ)-like and proliferative dark zone (DZ)-like germinal center B (GCB) cells. The GCB cells in AITL clonally evolved with recurrent mutations in genes related to core histones. In silico network analysis using scRNA-seq data identified Cd40-Cd40lg as a possible mediator of GCB and tumor cell cluster interactions. Treatment of AITL model mice with anti-Cd40lg inhibitory antibody prolonged survival. The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40-CD40LG axis.
Authors’ Reply: Understanding the Multiple Roles of Extracellular Histones in Mediating Endothelial Dysfunction
Authors: Lara Zafrani, Marine Arnaud, Nuala Mooney
Journal: Journal of the American Society of Nephrology (2022)

We would like to thank Tinghang et al. for their interest in our manuscript and their constructive comments. In their letter, they underline information regarding the role of extracellular histones on endothelial cytotoxicity. Indeed, they refer to the work of Karki and coworkers1 that reported data from studies in pulmonary artery endothelial cells, which were similar to the data we have obtained in a human microvascular endothelial cell line and in primary human renal glomerular endothelial cells, i.e., the ability of histones H3 and H4 to induce an inflammatory response and to increase endothelial permeability and the implication of Toll-like receptor 4. In keeping with our in vivo results showing an increase in peritubular endothelial permeability in mice with tumor lysis syndrome and mice injected with histones,2 they report that the histone subunits H3 and H4 cause endothelial barrier disruption and a decrease in vascular endothelial (VE)-cadherin expression in pulmonary endothelial cells. Disassembly of adherence junctions compromised by the integrity of the VE-cadherin adhesion complex has been described in many pathologic conditions associated with increased endothelial permeability. However, data on pulmonary endothelial cells should be interpreted with caution in the specific context of AKI due to the high degree of heterogeneity of vascular endothelial cells in different organs. Indeed, whereas the pulmonary endothelium is a continuous vascular endothelium, fenestrated endothelial cells are seated within the glomeruli and tubuli of the kidney. In human renal glomerular cells and human dermal microvascular cells, we did not observe any change in CD144 (VE-cadherin) staining after H3 stimulation. The discrepancy with the results mentioned by Tinghang et al.1,3 may be due to dissimilar expression of VE-cadherin according to endothelial cell subtypes and/or organs.4 Beyond the role of VE-cadherin, LPS-induced disruption of other tubular tight junction proteins, including zonula occludens-1, occludin, and claudins, via a Toll-like receptor 4–dependent mechanism, has also been involved in endotoxemic-mediated AKI.5,6 This could represent yet another promising pathway of investigation to decipher the mechanisms underpinning the increase of peritubular permeability induced by extracellular histones. Overall, the published data mentioned by Tinghang et al. add further information to our results concerning the potential role of extracellular histones in endothelial permeability that may be involved in organ failure in various pathologic conditions, including tumor lysis syndrome. Disclosures L. Zafrani reports receiving research funding from Jazz Pharmaceuticals. All remaining authors have nothing to disclose. Funding None.
Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas
Authors: Masahiro Chiba, Joji Shimono, Takashi Ishio, Norio Takei, Kohei Kasahara, Reiki Ogasawara, Takahide Ara, Hideki Goto, Koh Izumiyama, Satoko Otsuguro, Liyanage P. Perera, Hiroo Hasegawa, Michiyuki Maeda, Satoshi Hashino, Katsumi Maenaka, Takanori Teshima, Thomas A. Waldmann, Yibin Yang, Masao Nakagawa
Journal: Blood (2022)

Adult T-cell leukemia/lymphoma (ATLL) is one of the aggressive peripheral T-cell neoplasms with a poor prognosis. Accumulating evidence demonstrates that escape from adaptive immunity is a hallmark of ATLL pathogenesis. However, the mechanisms by which ATLL cells evade natural killer (NK)-cell-mediated immunity have been poorly understood. Here we show that CD48 expression in ATLL cells determines the sensitivity for NK-cell-mediated cytotoxicity against ATLL cells. We performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening using 2 ATLL-derived cell lines and discovered CD48 as one of the best-enriched genes whose knockout conferred resistance to YT1-NK cell line-mediated cytotoxicity. The ability of CD48-knockout ATLL cells to evade NK-cell effector function was confirmed using human primary NK cells with reduced interferon-γ (IFNγ) induction and degranulation. We found that primary ATLL cells had reduced CD48 expression along with disease progression. Furthermore, other subgroups among aggressive peripheral T-cell lymphomas (PTCLs) also expressed lower concentrations of CD48 than normal T cells, suggesting that CD48 is a key molecule in malignant T-cell evasion of NK-cell surveillance. Thus, this study demonstrates that CD48 expression is likely critical for malignant T-cell lymphoma cell regulation of NK-cell-mediated immunity and provides a rationale for future evaluation of CD48 as a molecular biomarker in NK-cell-associated immunotherapies.
The Potential for Pragmatic Trials to Reduce Racial and Ethnic Disparities in Kidney Disease
Authors: Laura M. Dember
Journal: Journal of the American Society of Nephrology (2022)

The well-documented and unacceptable racial and ethnic disparities in the prevalence and outcomes of kidney disease are receiving increased attention within and beyond the nephrology community, with numerous calls for intentional, active approaches to ensure that care is equitable and that
Modeling spatial interaction networks of the gut microbiota
Authors: Xiaocang Cao, Ang Dong, Guangbo Kang, Xiaoli Wang, Liyun Duan, Huixing Hou, Tianming Zhao, Shuang Wu, Xinjuan Liu, He Huang, Rongling Wu
Journal: Gut Microbes (2022)

How the gut microbiota is organized across space is postulated to influence microbial succession and its mutualistic relationships with the host. The lack of dynamic or perturbed abundance data poses considerable challenges for characterizing the spatial pattern of microbial interactions. We integrate allometric scaling theory, evolutionary game theory, and prey-predator theory into a unified framework under which quasi-dynamic microbial networks can be inferred from static abundance data. We illustrate that such networks can capture the full properties of microbial interactions, including causality, the sign of the causality, strength, and feedback loop, and are dynamically adaptive along spatial gradients, and context-specific, characterizing variability between individuals and within the same individual across time and space. We design and conduct a gut microbiota study to validate the model, characterizing key spatial determinants of the microbial differences between ulcerative colitis and healthy controls. Our model provides a sophisticated means of unraveling a complete atlas of how microbial interactions vary across space and quantifying causal relationships between such spatial variability and change in health state.
Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance
Authors: Violeta Serra, Anderson T. Wang, Marta Castroviejo-Bermejo, Urszula M. Polanska, Marta Palafox, Andrea Herencia-Ropero, Gemma N. Jones, Zhongwu Lai, Joshua Armenia, Filippos Michopoulos, Alba Llop-Guevara, Rachel Brough, Aditi Gulati, Stephen J. Pettitt, Krishna C. Bulusu, Jenni Nikkilä, Zena Wilson, Adina Hughes, Paul W.G. Wijnhoven, Ambar Ahmed, Alejandra Bruna, Albert Gris-Oliver, Marta Guzman, Olga Rodríguez, Judit Grueso, Joaquin Arribas, Javier Cortés, Cristina Saura, Alan Lau, Susan Critchlow, Brian Dougherty, Carlos Caldas, Gordon B. Mills, J. Carl Barrett, Josep V. Forment, Elaine Cadogan, Christopher J. Lord, Cristina Cruz, Judith Balmaña, Mark J. O'Connor
Journal: Clinical Cancer Research (2022)

PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance.
Minimal residual disease–driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL
Authors: Lydia Scarfò, Silvia Heltai, Elisa Albi, Eloise Scarano, Luana Schiattone, Lucia Farina, Riccardo Moia, Marina Deodato, Andrea Ferrario, Marina Motta, Gianluigi Reda, Rosaria Sancetta, Marta Coscia, Paolo Rivela, Luca Laurenti, Marzia Varettoni, Eleonora Perotta, Antonella Capasso, Pamela Ranghetti, Maria Colia, Paolo Ghia
Journal: Blood (2022)
Mortality after transjugular intrahepatic portosystemic shunt in older adult patients with cirrhosis: A validated prediction model
Authors: Francesco Vizzutti, Ciro Celsa, Vincenza Calvaruso, Marco Enea, Salvatore Battaglia, Laura Turco, Marco Senzolo, Silvia Nardelli, Roberto Miraglia, Davide Roccarina, Claudia Campani, Dario Saltini, Cristian Caporali, Federica Indulti, Stefano Gitto, Alberto Zanetto, Gabriele Di Maria, Marcello Bianchini, Maddalena Pecchini, Silvia Aspite, Chiara Di Bonaventura, Michele Citone, Tomas Guasconi, Fabrizio Di Benedetto, Umberto Arena, Fabrizio Fanelli, Luigi Maruzzelli, Oliviero Riggio, Patrizia Burra, Antonio Colecchia, Erica Villa, Fabio Marra, Calogero Cammà, Filippo Schepis
Journal: Hepatology (2022)

Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults.We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis.After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted.
Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH)
Authors: Zhenwei Peng, Wenzhe Fan, Bowen Zhu, Guoying Wang, Junhui Sun, Chengjiang Xiao, Fuxi Huang, Rong Tang, Yu Cheng, Zhen Huang, Yuchuang Liang, Huishuang Fan, Liangliang Qiao, Fuliang Li, Wenquan Zhuang, Baogang Peng, Jiping Wang, Jiaping Li, Ming Kuang
Journal: Journal of Clinical Oncology (2022)

PURPOSE Lenvatinib (LEN) is a first-line therapy for patients with advanced hepatocellular carcinoma (HCC); however, it has shown modest survival benefits. Therefore, we aimed to compare clinical outcomes of LEN combined with transarterial chemoembolization (LEN-TACE) versus LEN monotherapy in patients with advanced HCC. MATERIALS AND METHODS This was a multicenter, randomized, open-label, parallel group, phase III trial. Patients with primary treatment-naive or initial recurrent advanced HCC after surgery were randomly assigned (1:1) to receive LEN plus on-demand TACE (LEN-TACE) or LEN monotherapy. LEN was initiated within 3 days after random assignment (initial dose: 12 mg once daily for patients ≥ 60 kg; 8 mg once daily for patients &lt; 60 kg). TACE was initiated one day after LEN initiation. The primary end point was overall survival (OS). RESULTS Between June 2019 and July 2021, a total of 338 patients underwent random assignment at 12 centers in China: 170 to LEN-TACE and 168 to LEN. At a prespecified event-driven interim analysis after a median follow-up of 17.0 months, the median OS was significantly longer in the LEN-TACE group (17.8 v 11.5 months; hazard ratio, 0.45; P &lt; .001). The median progression-free survival was 10.6 months in the LEN-TACE group and 6.4 months in the LEN group (hazard ratio, 0.43; P &lt; .001). Patients in the LEN-TACE group had a higher objective response rate according to the modified RECIST (54.1% v 25.0%, P &lt; .001). Multivariable analysis revealed that portal vein tumor thrombus and treatment allocation were independent risk factors for OS. CONCLUSION The addition of TACE to LEN improves clinical outcomes and is a potential first-line treatment for patients with advanced HCC.
Overall Survival, Progression-Free Survival, and Tumor Response Benefit Supporting Initial US Food and Drug Administration Approval and Indication Extension of New Cancer Drugs, 2003-2021
Authors: Daniel Tobias Michaeli, Thomas Michaeli
Journal: Journal of Clinical Oncology (2022)

Clinical trial evidence is routinely evaluated for initial drug approvals, yet the benefit of indication extensions remains uncertain. This study evaluates the clinical benefit supporting new cancer drugs' initial and supplemental US Food and Drug Administration (FDA) indication approval. Clinical trial evidence supporting each indication's FDA approval was collected from the Drugs@FDA database between 2003 and 2021. Drug, indication, and clinical trial characteristics are described. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk for tumor response were meta-analyzed. Out of 124 FDA-approved drugs, 78 were approved across multiple indications. Out of 374 indications, 141 were approved as combination therapies, 255 for solid cancers, 121 with biomarkers, and 182 as first-line therapy. Approval was mostly supported by open-label (267 [71%]) phase III (238 [64%]) concurrent randomized controlled trials (248 [66%]) with a median of 331 enrolled patients (interquartile range [IQR], 123-665 patients). Across 234 randomized controlled trials with available data, drugs' HRs were 0.73 (95% CI, 0.72 to 0.75; I2 = 29.6%) for OS and 0.57 (95% CI, 0.54 to 0.60; I2 = 90.6%) for PFS, whereas tumor response was 1.38 (95% CI, 1.33 to 1.42; I2 = 80.7%). Novel pharmaceuticals increased patient survival by a median of 2.80 months (IQR, 1.97-4.60 months) for OS and 3.30 months (IQR, 1.50-5.58 months) for PFS. Initial indications more frequently received accelerated approval, supported by single-arm trials for advanced-line monotherapies, than indication extensions. Initial approvals provided a higher PFS (HR, 0.48 v 0.58; P = .002) and tumor response (relative risk, 1.76 v 1.36; P < .001). New cancer drugs substantially reduce the risk of death and tumor progression, yet only marginally extend patient survival. The FDA, physicians, patients, and insurers must evaluate and decide on a drug's safety and efficacy approval, pricing, coverage, and reimbursement on an indication-specific level.
Phototherapy with Cancer-Specific Nanoporphyrin Potentiates Immunotherapy in Bladder Cancer
Authors: Zheng Zhu, Ai-Hong Ma, Hongyong Zhang, Tzu-Yin Lin, Xiangdong Xue, Hizra Farrukh, Shaoming Zhu, Wei Shi, Ruan Yuan, Zhixiu Cao, Veera Chandra Sekhar Reddy Chittepu, Rao Prabhala, Yuanpei Li, Kit S. Lam, Chong-xian Pan
Journal: Clinical Cancer Research (2022)

Immune checkpoint inhibitors (ICI) in general have shown poor efficacy in bladder cancer. The purpose of this project was to determine whether photodynamic therapy (PDT) with bladder cancer-specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI.